A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese

被引：43

作者：

Iida, Aritoshi

Takahashi, Atsushi ^{[2
]}

Kubo, Michiaki ^{[3
]}

Saito, Susumu ^{[3
]}

Hosono, Naoya ^{[3
]}

Ohnishi, Yozo ^{[3
]}

Kiyotani, Kazuma ^{[4
]}

Mushiroda, Taisei ^{[4
]}

Nakajima, Masahiro

Ozaki, Kouichi ^{[5
]}

Tanaka, Toshihiro ^{[5
]}

Tsunoda, Tatsuhiko ^{[6
]}

Oshima, Shuichi ^{[8
]}

Sano, Motoki ^{[9
]}

Kamei, Tetsumasa ^{[10
]}

Tokuda, Torao ^{[11
]}

Aoki, Masashi ^{[12
]}

Hasegawa, Kazuko ^{[13
]}

Mizoguchi, Koichi ^{[14
]}

Morita, Mitsuya ^{[15
]}

Takahashi, Yuji ^{[16
]}

Katsuno, Masahisa ^{[17
,18
]}

Atsuta, Naoki ^{[17
]}

Watanabe, Hirohisa ^{[17
]}

Tanaka, Fumiaki ^{[17
]}

Kaji, Ryuji ^{[19
]}

Nakano, Imaharu ^{[15
]}

Kamatani, Naoyuki ^{[2
]}

Tsuji, Shoji ^{[16
]}

Sobue, Gen ^{[17
]}

Nakamura, Yusuke ^{[7
,20
]}

Ikegawa, Shiro ^{[1
]}

机构：

[1] RIKEN, Lab Bone & Joint Dis, Ctr Genom Med, Minato Ku, Tokyo 1088639, Japan

[2] RIKEN, Lab Stat Anal, Ctr Genom Med, Tokyo 1088639, Japan

[3] RIKEN, Lab Genotyping Dev, Ctr Genom Med, Yokohama, Kanagawa 2300045, Japan

[4] RIKEN, Lab Pharmacogenet, Ctr Genom Med, Yokohama, Kanagawa 2300045, Japan

[5] RIKEN, Lab Cardiovasc Dis, Ctr Genom Med, Yokohama, Kanagawa 2300045, Japan

[6] RIKEN, Lab Med Informat, Ctr Genom Med, Yokohama, Kanagawa 2300045, Japan

[7] RIKEN, Lab Int Alliance, Ctr Genom Med, Yokohama, Kanagawa 2300045, Japan

[8] Chiba Tokushukai Hosp, Dept Neurosurg, Funabashi, Chiba 2748503, Japan

[9] Chibanishi Gen Hosp, Dept Neurol, Matsudo, Chiba 2702251, Japan

[10] Chigasaki Tokushukai Gen Hosp, Dept Neurol, Chigasaki, Kanagawa 2538558, Japan

[11] Tokushukai Grp, Tokyo 1020093, Japan

[12] Tohoku Univ, Dept Neurol, Sch Med, Sendai, Miyagi 9808574, Japan

[13] Sagamihara Natl Hosp, Dept Neurol, Natl Hosp Org, Sagamihara, Kanagawa 2288522, Japan

[14] Shizuoka Inst Epilepsy & Neurol Disorders, Dept Neurol, Shizuoka 4208688, Japan

[15] Jichi Med Univ, Div Neurol, Dept Med, Shimotsuke 3290498, Japan

[16] Univ Tokyo, Grad Sch Med, Dept Neurol, Tokyo 1138655, Japan

[17] Nagoya Univ, Dept Neurol, Grad Sch Med, Nagoya, Aichi 4668550, Japan

[18] Nagoya Univ, Inst Adv Res, Nagoya, Aichi 4668550, Japan

[19] Univ Tokushima, Grad Sch Med, Dept Neurol, Tokushima 7708503, Japan

[20] Univ Tokyo, Inst Med Sci, Dept Mol Med, Ctr Human Genome, Tokyo 1088639, Japan

来源：

HUMAN MOLECULAR GENETICS | 2011年 / 20卷 / 18期

关键词：

GENOME-WIDE ASSOCIATION; HEAVY NEUROFILAMENT SUBUNIT; MOTOR-NEURON DISEASE; RISK-FACTOR; GENE; MUTATIONS; TGF-BETA-1; PROTEIN; ONSET; ALS;

D O I：

10.1093/hmg/ddr268

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P = 9.3 x 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-beta (TGF-beta) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-beta signaling and that decreased ZNF512B expression increases susceptibility to ALS.

引用

页码：3684 / 3692

页数：9

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